Vasoconstrictor composition



Patented Mar. 15, 1949 VASOCONSTRICTOR COMPOSITION Gordon A. Alles, SanMarino, Calif., assignor to Smith, Kline & French Laboratories,Philadelphia, Pa., a corporation of Pennsylvania N Drawing. ApplicationOctober 18, 1943, Serial No. 506,754

12 Claims. 1

This invention relates to a medical preparation, and particularly to amedical preparation suitable for topical application to the mucosa toeffect vasoconstriction.

The principal object of this invention is to provide a new andadvantageous medical preparation .suitable for such application.

This application is a continuation-in-part of my applications Ser. Nos.461,451 and 461,452, filed October 9, 1942, both noW abandoned.

The new medical preparation in accordance with this invention is usefulfor efiecting vasoconstriction in the mucosal membranes of the body andresults therefrom. In accordance with this invention a novel andefiective remedy is provided for use in the treatment of congestions ofthe nasal or bronchial airway and its connecting sinuses, such as occurwith colds, sinusitis, hay fever, bronchial asthma and similarinflammatory conditions. It is also notably effective when applied tothe conjunctiva of the eye. The

remedy acts to cause constriction of the smaller blood vessels of themucosa with consequent shrinkage of the tissue and drainage of edemaamounts suflicient to produce marked vasconstrictor effect in themucosal membranes do not produce any notable efiect upon the centralnervous system. The complete systemic absorption of very consciderableamounts of the active ingredient has only moderate effects upon thegeneral circulation of the body. By reason of these novelcharacteristics this medical preparation is particularly useful in localtreatment of the nasal or bronchial mucosa and when locally applied to:the eye eXerts notable vasoconstrictor action.

.The new medical preparation in accordance with this invention comprisesa bland solution compatible with the mucous membrane and containing asan eifective ingredient a salt of an aemethylhexylamine selected fromthe group consisting of e-methyl-normal-hexylamine.

CH3.CH2.CH2.CH2.CH2.CH(NH2) .CH3

and a-methyl-iso-hexylamine,

CI'L'LCH (CH3) .CH2.CH2.CH (NI-I2) .CI-Is more particularly, such amedical preparation contains from 0.01 to 0.3 gram-equivalent per literof a salt of the a-methylhexylamine, such as the chloride, sulfate,tartrate, or oleate, insolution in a liquid suitable for application tothe mucosal membranes such as a neutral or weakly acidic aqueous liquidor oil. These salts may be used in either their optically active orracemic forms.

Following the observations of others, I have found that while a numberof primary-carbin alkylamines do have some vasoconstrictor effect, thisaction is of short duration and no considerable and prolongedvasoconstriction results from various modes of application. While someobservations have been made by others of the effect of a fewsecondary-carbin alkylamines after intravenous injection into animals,none of these were found to exert sufiiciently notable and prolongedvasoconstrictor effect to be suitable for a medical preparation. I havediscovered that a-methyl-normal-hexylamine and oz-l'llthYl-lSO-hexylamine are far more active than any secondary-carbin alkylaminespreviously studied by others and that these a-methylhexylamines areadvantageously suitable for medical preparations when used in compoundedsolutions of proper concentration range. Solutions of such anumethylhexylamine when topically applied to mucosal membranes, such asthe nasal membranes or the surface of the eye, cause prolongedvasoconstriction and this action extends deeply into the tissues for theeffective ingredient is absorbed without considerable destruction.

While for topical application a solution of a salt ofa-methyl-normal-hexylamine or of u-methylisohexylamine containing but0.01 gram-equivalent per liter causes a considerable vasoconstriction,higher concentrations with their greater and more prolonged effects aremore generally suitable.

A suitable vasoconstrictor composition in accordance with this inventionmay comprise a bland aqueous or oil solution compatible with the mucuousmembrane, containing a salt of the a-methylhexylamine dissolved in amany-fold greater amount of an aqueous solvent or oil.

Such a composition in the form of an aqueous solution may be prepared bydissolving the amine salt in a many-fold greater amount of a blandaqueous vehicle compatible with the mucous membrane. Preferred examplesof aqueous vehicles that may be employed are aqueous solutionscontaining suitable concentrations of solutes having therapeuticproperties and compatible with the functioning of the mucous membrane,such as'boric acid or sodium chloride.

For example, I have found that a bland aqueous solution containing '1vor 2 grams of the sulfate of 4 culatory actions such ana-methylhexylamine in 100 milliliters of saturated boric acid solutionin water, is most generally suitable. These concentrations correspond to0.06 and 0.12 gram-equivalent per liter, respectively, and comparableconcentrations of other a-methylhexylamine salts may be equivalentlyemployed. For a particularly intense shinkage an aqueous solutioncontaining as much as 0.3 gram-equivalent of the salt per liter, thoughhypertonic in ionic strength, may be desirably used without anyconsiderable irritant effect. Solutions in aqueous liquids containingless than 0.15 gram-equivalent per liter of the effective ingredient aredesirably brought up to such ionic strength by the addition of sodiumchloride or any physiologically compatible mixture of salts.

Oil solutions are on occasion suitable for application in the nose, suchas a preparation containing an a-methylhexylamine oleate dissolved in amany-fold greater amount of a bland oil vehicle compatible with themucous membrane. A generally suitable medical preparation of this typeis made by dissolving 1 gram of an a-methylhexylamine base in 100milliliters of light liquid petrolatum or refined vegetable oil togetherwith an equivalent or slight excess of oleic acid to form the oleate,though concentrations of the active ingredient of but half or twice thismay be desirably uesful. Such concentrations represent a range of fromabout 0.05 to 0.2 gram-equivalent per liter of the salt.

The topical application of a milliliter or at most two or threemilliliters of these medicinal preparations containin from 0.01 to 0.3gramequivalent per liter of a salt of an e-methylhexylamine suffices toproduce a fully effective local vasoconstriction. No notable circulatoryor central nervous system stimulant effects will result from theapplication of such dosages to the mucosa. Observations with regard tothe systemic effects of a-methyl-normal-hexylamine anda-methyl-iso-hexylamine have shown that following the completeabsorption of as much as 100 milligrams of the sulfates of these amines(corresponding to 0.6 milligram-equivalent) there may be a justdetectable rise in blood pressure. Following absorption of 200milligrams of these salts there results a moderate increase in bloodpressure and reflex slowing of the heart rate. No central nervous systemeifects are to be noted after any such dosages of these compounds.Systemic absorption of such dosages from local applications to themucosa of the nose or eye could only occur from solutions of suitableconcentration with amounts in excess of those required for theproduction of a full local vasoconstriction effect and even then theresultant cirrepresent no considerable hazard.

The effective ingredient of the medical preparation may be prepared byknown procedures. Thus for example, a-methyl-normal-hexylamine base maybe prepared by the catalytic reduction of methyl amyl ketoxime withhydrogen or by reduction with metallic sodium in ethanol or butanol, andsimilarly methyl isoamyl ketoxime may be reduced to forma-methyl-iso-hexylamine base. The a-methyl-normal-hexylamine base whenpure boils about 141-442 C. and the a-methyl-iso-hexylamine base boilsabout 137 C. These bases may be put directly into solution in water orother suitable solvent and then made into neutral or slightly acidicsolution of a salt by addition of an equivalent of an acid such ashydrochloric, sulfuric, tartaric or oleic. Thes bases form hygroscopicchlorides which are somewhat difiicult to handle as solids, but form airstable sulfates which melt only above about 250-260 with decomposition.The sulfates are particularly desirable for use in medical preparationsbecause of their ease of crystallization from suitable solvents such aswater-ethanol mixtures. Bitartrates of these a-methylhexylamines havebeen found to be readily formed and crystallize well. The racemic aminesmay be resolved into their optically active forms by crystallizing theird-tartaric and l-tartaric acid salts from ethanol and then liberatingthe optically active amines or these salts may be directly used for themaking of suitable medical preparations. The oleates of thea-methylhexylamines are best made in connection with the compounding oftheir solutions suitable for medical preparations.

I claim:

1. A vasoconstrictor composition comprising a salt of ana-methylhexylamine of the group consisting of a-methyl-normal-hexylamineand a-methyl-iso-hexylamine dissolved in a manyfold greater amount of abland vehicle compatible with the mucous membrane.

2. A vasoconstrictor composition as set forth in claim 1, in which thebland vehicle is an aqueous solution of a substance having therapeuticproperties.

3. A vasoconstrictor composition, comprising a salt ofa-methyl-normal-hexylamine dissolved in a many-fold greater amount of abland vehicle compatible with the mucous membrane a 4. A vasoconstrictorcomposition as set forth in claim 3, in which the bland vehicle is anaqueous solution of a substance having therapeutic properties.

5. A vasoconstrictor composition as set forth in claim 3, in which thesalt of a-methyl-normalhexylamine is a-methy1-normal-hexylamine sulfate.

6. A vasoconstrictor composition comprising a bland aqueous solutioncompatible with the mucous membrane, containinga-methyl-normalhexylamine sulfate dissolved in a many-fold greateramount of the aqueous solvent.

7. A vasoconstrictor composition comprising a bland aqueous solutioncompatible with the mucous membrane, containing about one to two percent of a-methyl-norma1-hexylamine sulfate.

8. A vasoconstrictor composition comprising a salt of a-methyl-iso-hexylamine dissolved in a many-fold greater amount of a bland vehiclecompatible with the mucous membrane.

9. A vasoconstrictor composition as set forth in claim 8, in which thebland vehicle is an aqueous solution of a substance having therapeuticproperties.

10. A vasoconstrictor composition as set forth in claim 8, in which thesalt of a-methyl-isohexylamine is a-methyl-iso-hexylamine sulfate.

11. A vasoconstrictor composition comprising a bland aqueous solutioncompatible with the mucous membrane, containing a-methyl-isohexylaminesulfate dissolved in a many-fold greater amount of the aqueous solvent.

12. A vasoconstrictor composition comprising a bland aqueous solutioncompatible with the mucous membrane. containing about one to two percentof m-methyl-iso-hexylamine sulfate.

GORDON A. ALLES.

(References on following page) 5 6 REFERENCES CITED Chemical Abstracts,vol. 15, page 2063. The following references are of record in the Dunkeret Joum' Amer Pharm' Assn file of this patent. (1941),v01. 30, pages619-623.

Proetz: Annals of Otology, Phinology and UNITED STATES PATENTS 5Laryng., Mar. 1942, vol. 51, pages 112-116. Number Name Date Tainter:Arch. Internat. de Pharmcodynamie 2,256 434 Klavehn Sept. 16 1941 et deTherapie, (1933), v01. 46, pages 223 to 226. 2,350,318 Shonle May 30,1944 OTHER REFERENCES 10 Beilsteins Handbuch Organische Chemie, 4th ed,vol. 4, pages 194, 195, 196.

